Review
SoxE factors: Transcriptional regulators of neural differentiation and nervous system development

https://doi.org/10.1016/j.semcdb.2016.08.013Get rights and content

Highlights

  • SoxE proteins influence many aspects of nervous system development.

  • SoxE proteins interact cell- and stage-specifically with transcription factors.

  • SoxE proteins recruit chromatin modifiers and accessory transcriptional machinery.

  • SoxE proteins regulate microRNA expression.

  • SoxE proteins establish multiple regulatory feedforward and feedback loops.

Abstract

Sox8, Sox9 and Sox10 represent the three vertebrate members of the SoxE subclass of high-mobility-group domain containing Sox transcription factors. They play important roles in the peripheral and central nervous systems as regulators of stemness, specification, survival, lineage progression, glial differentiation and homeostasis. Functions are frequently overlapping, but sometimes antagonistic. SoxE proteins dynamically interact with transcriptional regulators, chromatin changing complexes and components of the transcriptional machinery. By establishing regulatory circuits with other transcription factors and microRNAs, SoxE proteins perform divergent functions in several cell lineages of the vertebrate nervous system, and at different developmental stages in the same cell lineage. The underlying molecular mechanisms are the topic of this review.

Introduction

The SoxE group is a subclass of the Sox family of transcription factors whose members are characterized by a sequence-specific DNA-binding high mobility group (HMG) domain first found in the mammalian sex determining gene Sry [1]. In most vertebrates, the SoxE group has three members, Sox8, Sox9 and Sox10, whereas invertebrates usually have a single SoxE protein [2]. Sequence conservation among SoxE proteins is much higher than with other Sox proteins, and particularly prominent in functionally relevant domains that comprise from N- to C-terminus a dimerization domain, the HMG domain, a central protein interaction domain (named K2) [3], [4] and the C-terminal transactivation domain (Fig. 1A). Although SoxE proteins are not confined to a single cell-type or tissue, they exhibit restricted expression patterns and serve essential functions in a limited number of developmental processes and adult tissues [1], [2].

This review will be mainly about SoxE proteins in the nervous system. As functions and mechanisms differ between peripheral nervous system (PNS) and central nervous system (CNS), we will discuss them consecutively. We will restrict ourselves to vertebrate SoxE proteins and if not stated otherwise refer to mouse proteins which are thought to function as their orthologs in other mammals. Rather than simply discussing functions, we will place our emphasis on the molecular mechanisms of SoxE proteins in their respective regulatory networks.

Section snippets

SoxE proteins and PNS

SoxE proteins are neural crest (NC) specifiers downstream of and induced by neural plate border specifiers in vertebrates. In cooperation with other NC specifiers such as FoxD3, Twist, Snail and Id proteins and depending on phosphorylation and sumoylation events, they convey upon cells in the neural plate border region NC cell identity, ensure survival and confer the ability to undergo epithelial-to-mesenchymal transition [5], [6], [7] (Fig. 1B). In mammals, Sox9 precedes Sox8 and Sox10, and

SoxE proteins and CNS

While present at the very onset of PNS development, SoxE proteins are missing in the early CNS. Neither neural plate nor early neural tube cells express SoxE proteins—with the exception of those that become NC (see above). Instead SoxB factors Sox2 and Sox3 prevail [52]. They may be involved in SoxE gene induction and remain expressed with SoxC, SoxD and SoxE proteins during further CNS development.

At early stages, neuroepithelial cells self-renew or give rise to neurons, but not glia. In that

Conclusions

While functions of SoxE proteins in PNS and CNS have been largely determined in the 1990s and early 2000s, the last ten years have provided substantial insights into the molecular mechanisms that underlie these functions. SoxE proteins interact with and exploit the help of a large number of transcription factors that vary with cell type and developmental stage [84]. They furthermore influence chromatin structure by recruiting chromatin modifying and remodelling machinery. Even their impact on

Acknowledgements

We apologize to all whose contributions were not cited due to space limitations. The authors’ work is supported by grants from the DFG (We1326/8, We1326/11 and We1326/12), the Bavarian State Ministry of Education and Culture, Science and Arts in the framework of the Bavarian Research Network Induced Pluripotent Stem Cells (ForIPS), and the IZKF (TP E18 and D24).

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